L-leucine alters pancreatic β-cell differentiation and function via the mTor signaling pathway

Leucine (Leu) is an essential branched-chain amino acid, which activates the mammalian target of rapamycin (mTOR) signaling pathway. The effect of Leu on cell differentiation during embryonic development is unknown. Here, we show that Leu supplementation during pregnancy significantly increased fetal body weight, caused fetal hyperglycemia and hypoinsulinemia, and decreased the relative islet area. We also used rat embryonic pancreatic explant culture for elucidating the mechanism of Leu action on β-cell development. We found that in the presence of Leu, differentiation of pancreatic duodenal homeobox-1-positive progenitor cells into neurogenin3-positive endocrine progenitor cells was inefficient and resulted in decreased β-cell formation. Mechanistically, Leu increases the intracellular levels of hypoxia-inducible factor 1-α, a repressor of endocrine fate in the pancreas, by activating the mTOR complex 1 signaling pathway. Collectively, our findings indicate that Leu supplementation during pregnancy could potentially increase the risk of type 2 diabetes mellitus by inhibiting the differentiation of pancreatic endocrine progenitor cells during a susceptible period of fetal life.